Transmethylation of cellular constituents has been associated with several diseased states; e.g. biogenic amines and schizophrenia. A detailed knowledge of the chemical mechanism by which such processes take place should allow us to design drugs that could block the transmethylation pathyway(s) of interest. During the current period of support (07-09 year) we have continued to study the chemical mechanism by which transalkylation reactions of sulfonium compounds are effected. We have also continued our studies of the in vivo effects of methylase inhibitors in several selected cell culture systems, and have synthesized the first of a series of sulfonium compounds containing both the catecholamine and nucleoside moieties as potential transition-state analog inhibitors of catechol-O-methyltransferase (COMT). During the coming period of support (10-12 year), we wish to continue our approach of using non-enzymic mechanistic studies, combined with kinetic and spectral probes of enzyme mechanism, to provide a rational basis for the design of inhibitors specific for a particular methylase; e.g. COMT. These highly specific inhibitors will then be investigated for use as pharmacological and biochemical tools, and for possible use as drugs in the treatment of diseases associated with the transmethylation process.